The present invention relates to novel pharmaceutical formulations comprising aminoalkyl phosphorothioate compounds. The formulations preferably include surfactants, hydrotropes and chelating agents to, inter alia, enhance the chemical and biological properties of the aminoalkyl phosphorothioate compounds.
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyo(copyright), NSC 296961, and WR-2721 and which will hereinafter be referred to as xe2x80x9camifostinexe2x80x9d) and other aminothiol compounds are disclosed in U.S. Pat. No. 3,892,824. These compounds were originally developed as antiradiation agents (radio-protectants), in particular to be used prior to exposure to x-ray or nuclear radiation, to protect against the harmful effects of such exposure which may be encountered during military conflicts.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant, i.e., as a protectant administered prior to therapy to reduce the undesirable adverse effects which arise during the use of chemotherapy and radiation therapy in the treatment of cancer. Nygaard et al., eds, Radioprotectors and Anticarcinogens, Academic Press, Inc., New York, pp. 73-85 (1983); Grdina et al., Carcinogenesis (London) 6:929-931 (1985). In addition, these compounds have been reported to afford protection against the adverse effects of chemotherapeutic agents, for example, alkylating agents such as cisplatin, when administered before or concurrently with the chemotherapeutic agent. Jordan et al., Exp. Mol. Pathol. 36:297 (1982); Doz et al., Cancer Chemother. Pharmacol. 28:308 (1991). Similarly, it has been reported that amifostine has been used experimentally prior to therapy to protect HIV-infected patients (AIDS) from the harmful side effects of 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT) therapy. International Published Application WO 90/14007, published Nov. 29, 1990. Amifostine and its derivatives have been shown to exert these reported protective effects without affecting the beneficial properties of the administered therapeutic agents. This is, in the case of chemotherapy, believed to be due to the selective uptake of the protective thiol and other metabolites into normal tissue. Yuhas, Cancer Res. 40:1519-1524 (1980); Yuhas, Cancer Treat. Rep. 63:971-976 (1979).
Amifostine is indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer. Physicians"" Desk Reference 53rd ed., p. 513-515 (1999).
Pharmaceutical compositions containing amifostine and a chelating agent to enhance gastrointestinal tract absorption of the active compound have been reported. Such compositions, suitable for oral or rectal administration, are described in U.S. Pat. No.5,167,947. Amifostine is also being developed for subcutaneous administration. See, International Publication No. WO98/34622. In its most common use, however, amifostine is administered parenterally, including by bolus injection and intravenous infusion. Since parenteral routes circumvent the protective barriers of the human body, exceptional purity of the dosage form must be achieved. Because the dosage form must be free of microorganisms and insoluble particulates, the process used in preparing it must embody Good Manufacturing Practices (xe2x80x9cGMPxe2x80x9d) that will produce and maintain the required quality of the product in terms of sterility and therapeutic effectiveness. Sterility is especially important in the treatment of cancer and AIDS patients, because in many instances they are already immuno-compromised and therefor highly susceptible to infections.
Amifostine has been sold as a sterile amorphous lyophilized powder containing active ingredient and mannitol. The mixture was supplied as a single use 10 ml vial containing 500 mg of amifostine and 500 mg of mannitol, and required reconstitution for intravenous infusion. Physicians"" Desk Reference, 51st ed. (1997) p. 485-486. Presently, a sterile crystalline dosage form of amifostine is sold under the trade name Ethyo(copyright). Physicians"" Desk Reference, 53rd ed. (1999) p. 513-515. A crystal structure and preparation of a dosage form, which exhibits greater thermal stability than the previously sold amorphous dosage form, is described by U.S. Pat. Nos. 5,424,471 and 5,591,731.
Intravenous administration of amifostine suffers from several serious drawbacks. First, administering compounds intravenously is extremely inconvenient, particularly when a daily dosing schedule for several weeks, or potentially several months in the case of myelodysplastic syndrome (xe2x80x9cMDSxe2x80x9d), is necessary, requiring a skilled practitioner to administer the dose. Second, when administered intravenously, patients suffer from dose-dependent undesirable side-effects such as nausea, vomiting, emesis and hypotension, as well as flushing or feeling of warmth, chills or feeling of coldness, dizziness, somnolence, hiccups and sneezing. A decrease in serum calcium concentration is a known pharmacological effect of intravenously administered amifostine. Allergic reactions ranging from mild skin rashes to rigors have also rarely occurred in conjunction with intravenously administered amifostine. At present, there are no known methods, other than co-administering agents such as anti-emetics, of reducing or avoiding these undesirable side effects. Third, there are related costs associated with intravenous administration, including personnel, equipment and medical measures to attenuate side effects.
Therefore, there remains a need for pharmaceutical delivery systems which are capable of delivering amifostine and related compounds to the patient in an effective, efficient and economical manner.
The present invention provides novel pharmaceutical formulations comprising aminoalkyl phosphorothioate compounds. The, pharmaceutical compositions of the present invention are efficacious formulations wherein the biological and/or chemical properties of the active agent are enhanced by the addition of ingredients including, but not limited to, one or more of the following: surfactants, chelating agents and hydrotropes. These additional formulation ingredients are considered to serve, individually or in combination, inter alia, to increase the biological activity or chemical properties of the active compound.
The novel pharmaceutical formulations of the invention may be administered to a mammal, including humans, to treat or prevent a variety of disorders associated with radiation or chemotherapy, and in a manner which decreases or reduces undesirable side effects associated with the compounds. In preferred embodiments, the formulations of the invention comprise amifostine, and the formulations are administered subcutaneously.
One aspect of the invention relates to pharmaceutical formulations comprising an aminoalkyl phosphorothioate and a surfactant alone. Such formulations, in accordance with the present invention, are considered to have improved chemical and biological properties. The invention also encompasses pharmaceutical formulations comprising an aminoalkyl phosphorothioate, a surfactant and a hydrotrope, wherein the hydrotrope, inter alia, enhances the solubility of the formulation composition. The invention further encompasses pharmaceutical formulations comprising an aminoalkyl phosphorothioate, a hydrotrope and a chelating agent. The formulations of the invention having a chelating agent are considered to have enhanced biological properties. This formulation is also considered to exhibit beneficial chemical and manufacturing properties, including, inter alia, improving freeze-drying procedures and freeze-drying itself. The invention further encompasses pharmaceutical formulations comprising an aminoalkyl phosphorothioate, a surfactant, a hydrotrope, and a chelating agent.
The subcutaneous route of administration leads to a limitation in the volume of the pharmaceutical formulation used due to distention of the skin at the injection site and associated pain. Thus, the present invention has a further benefit of increasing the solubility of the active compounds in the pharmaceutical compositions of the invention, such that a greater amount of active compound can be administered per dose, without additional pain at the injection site.
Another aspect of the invention relates to sterile dosage forms of the above-described pharmaceutical compositions. The pharmaceutical compositions of the present invention may be in liquid or solid forms suitable for reconstitution such as freeze-dried or lyophilized forms, although the invention includes non-freeze-dried solids. The pharmaceutical composition may comprise a single dosage form which comprises all the components of the composition. Alternatively, the invention encompasses a dosage form kit wherein the aminoalkyl phosphorothioate compound and the remaining components of the formulation composition are provided in separate containers, and a solution for use is prepared by combining the formulation ingredients with a suitable carrier, such as sterile water prior to administration.
The pharmaceutical compositions of the invention comprising aminoalkyl phosphorothioate compounds may be adapted for administration to a patient in a number of ways, including, but not limited to parenteral (including subcutaneous, intravenous and intramuscular); or oral; mucosal (including buccal, sublingual, vaginal and rectal); topical, transdermal and the like. Subcutaneous administration is preferred.
The present invention is further directed to novel pharmaceutical compositions comprising aminoalkyl phosphorothioate and other active ingredients. Finally, the pharmaceutical compositions of the invention may also include solvents and co-solvents, excipients, antioxidants, carriers, diluents, buffers, bulking agents, solubilizers, wetting agents, suspending agents, emulsifiers and thickening agents.